multiple-micronutrient supplementation for women during pregnancy

Multiple-micronutrient supplementation for women during

pregnancy (Review)

Haider BA, Bhutta ZA

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2012, Issue 11

http://www.thecochranelibrary.com

Multiple-micronutrient supplementation for women during pregnancy (Review)

Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

16DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Multiple micronutrients versus controls (no supplements, placebo or two or less than two

micronutrients), Outcome 1 Preterm births. . . . . . . . . . . . . . . . . . . . . . . . 72


micronutrients), Outcome 2 Small-for-gestational age. . . . . . . . . . . . . . . . . . . . . 74


micronutrients), Outcome 3 Small-for-gestational age: maternal BMI. . . . . . . . . . . . . . . 75


micronutrients), Outcome 4 Small for gestational age: maternal height. . . . . . . . . . . . . . . 77


micronutrients), Outcome 5 Small-for-gestational age: supplementation. . . . . . . . . . . . . . 78


micronutrients), Outcome 6 Low birthweight. . . . . . . . . . . . . . . . . . . . . . . 79


micronutrients), Outcome 7 Low birthweight: maternal BMI. . . . . . . . . . . . . . . . . . 80


micronutrients), Outcome 8 Low birthweight: maternal height. . . . . . . . . . . . . . . . . 82


micronutrients), Outcome 9 Low birthweight: supplementation. . . . . . . . . . . . . . . . . 83


micronutrients), Outcome 10 Pre-eclampsia. . . . . . . . . . . . . . . . . . . . . . . . 84


micronutrients), Outcome 11 Miscarriage (loss before 28 weeks). . . . . . . . . . . . . . . . . 85


micronutrients), Outcome 12 Maternal mortality. . . . . . . . . . . . . . . . . . . . . . 86


micronutrients), Outcome 13 Perinatal mortality. . . . . . . . . . . . . . . . . . . . . . 87


micronutrients), Outcome 14 Stillbirths. . . . . . . . . . . . . . . . . . . . . . . . . 88


micronutrients), Outcome 15 Neonatal mortality. . . . . . . . . . . . . . . . . . . . . . 89

iMultiple-micronutrient supplementation for women during pregnancy (Review)



micronutrients), Outcome 16 Maternal anaemia (third trimester Hb < 110 g/L). . . . . . . . . . . . 90


micronutrients), Outcome 17 Placental abruption. . . . . . . . . . . . . . . . . . . . . . 91


micronutrients), Outcome 18 Very preterm birth (before 34 weeks of gestation). . . . . . . . . . . . 91


micronutrients), Outcome 19 Side effects of supplements. . . . . . . . . . . . . . . . . . . 92


micronutrients), Outcome 20 Congenital anomalies (including neural tube defects). . . . . . . . . . 92


micronutrients), Outcome 21 Neurodevelopmental outcome: BSID scores. . . . . . . . . . . . . 93

Analysis 2.1. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 1 Preterm births. . . . . . 94

Analysis 2.2. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 2 Small-for-gestational age. . 95

Analysis 2.3. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 3 Small-for-gestational age: maternal

BMI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Analysis 2.4. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 4 Small-for-gestational age: maternal

height. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Analysis 2.5. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 5 Small-for-gestational age:

supplementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Analysis 2.6. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 6 Low birthweight. . . . . 100

Analysis 2.7. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 7 Low birthweight: maternal

BMI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Analysis 2.8. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 8 Low birthweight: maternal

height. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Analysis 2.9. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 9 Low birthweight:


Analysis 2.10. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 10 Pre-eclampsia. . . . . 105

Analysis 2.11. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 11 Miscarriage (loss before 28

weeks). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Analysis 2.12. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 12 Maternal mortality. . . 107

Analysis 2.13. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 13 Perinatal mortality. . . 108

Analysis 2.14. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 14 Perinatal mortality: maternal

BMI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Analysis 2.15. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 15 Perinatal mortality: maternal

height. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Analysis 2.16. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 16 Perinatal mortality:


Analysis 2.17. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 17 Stillbirths. . . . . . 112

Analysis 2.18. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 18 Neonatal mortality. . . 113

Analysis 2.19. Comparison 2 Multiple micronutrients versus iron folate only, Outcome 19 Maternal anaemia (third

trimester Hb

[Intervention Review]

Multiple-micronutrient supplementation for women duringpregnancy

Batool A Haider1, Zulfiqar A Bhutta2

1Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA, USA. 2Division of Women and Child

Health, Aga Khan University Hospital, Karachi, Pakistan

Contact address: Zulfiqar A Bhutta, Division of Women and Child Health, Aga Khan University Hospital, Stadium Road, PO Box

3500, Karachi, 74800, Pakistan. [email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 11, 2012.

Review content assessed as up-to-date: 17 February 2012.

Citation: Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database of

Systematic Reviews 2012, Issue 11. Art. No.: CD004905. DOI: 10.1002/14651858.CD004905.pub3.


A B S T R A C T

Background

Multiple-micronutrient deficiencies often coexist in low- to middle-income countries. They are exacerbated in pregnancy due to the

increased demands, leading to potentially adverse effects on the mother. Substantive evidence regarding the effectiveness of multiple-

micronutrient supplements (MMS) during pregnancy is not available.

Objectives

To evaluate the benefits to both mother and infant of multiple-micronutrient supplements in pregnancy and to assess the risk of adverse

events as a result of supplementation.

Search methods

We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (17 February 2012) and reference lists of retrieved articles

and key reviews. We also contacted experts in the field for additional and ongoing trials.

Selection criteria

All prospective randomised controlled trials evaluating multiple-micronutrient supplementation during pregnancy and its effects on

the pregnancy outcome, irrespective of language or publication status of the trials. We included cluster-randomised trials but quasi-

randomised trials were excluded.

Data collection and analysis

Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted the data.

Data were checked for accuracy.

Main results

Twenty-three trials (involving 76,532 women) were identified as eligible for inclusion in this review but only 21 trials (involving 75,785

women) contributed data to the review.

When compared with iron and folate supplementation, MMS resulted in a statistically significant decrease in the number of low

birthweight babies (risk ratio (RR) 0.89; 95% confidence interval (CI) 0.83 to 0.94) and small-for-gestational age (SGA) babies (RR

1Multiple-micronutrient supplementation for women during pregnancy (Review)


0.87; 95% CI 0.81 to 0.95). No statistically significant differences were shown for other maternal and pregnancy outcomes: preterm

births RR 0.99 (95% CI 0.96 to 1.02), miscarriage RR 0.90 (95% CI 0.79 to 1.02), maternal mortality RR 0.97 (95% CI 0.63 to

1.48), perinatal mortality RR 0.99 (95% CI 0.84 to 1.16), stillbirths RR 0.96 (95% CI 0.86 to 1.07) and neonatal mortality RR 1.01

(95% CI 0.89 to 1.15).

A number of prespecified clinically important outcomes could not be assessed due to insufficient or non-available data. These include

placental abruption, congenital anomalies including neural tube defects, premature rupture of membranes, neurodevelopmental delay,

very preterm births, cost of supplementation, side-effects of supplements, maternal well being or satisfaction, and nutritional status of

children.

Authors conclusions

Though multiple micronutrients have been found to have a significant beneficial impact on SGA and low birthweight babies, we still

need more evidence to guide a universal policy change and to suggest replacement of routine iron and folate supplementation with a

MMS. Future trials should be adequately powered to evaluate the effects on mortality and other morbidity outcomes. Trials should also

assess the effect of variability between different combinations and dosages of micronutrients, keeping within the safe recommended

levels. In regions with deficiency of a single micronutrient, evaluation of each micronutrient against a placebo in women already

receiving iron with folic acid would be especially useful in justifying the inclusion of that micronutrient in routine antenatal care.

P L A I N L A N G U A G E S U M M A R Y

Multiple-micronutrient supplementation for women during pregnancy

In low- andmiddle-income countries, many women have poor diets and are deficient in nutrients andmicronutrients which are required

for good health. Micronutrients are vitamins and minerals that are needed by the body in very small quantities but are important for

normal functioning, growth and development. During pregnancy, these women often become more deficient, with the need to provide

nutrition for the baby too, and this can impact on their health and that of their babies. Combining multiple micronutrients has been

suggested as a cost-effective way to achieve multiple benefits for the women during pregnancy. Micronutrient deficiencies are known

to interact and a greater effect may be achieved by multiple supplementation rather than single nutrient supplementation, although

interactions may also lead to poor absorption of some of the nutrients. High doses of some nutrients may also cause harm to the mother

or her baby. Overall, multiple-micronutrient supplementation reduced the number of low birthweight and small-for-gestational age

babies when compared with supplementation with two or less micronutrients, iron and folic acid supplements, no supplementation or

a placebo. This review included 23 studies (involving 76,532 women) but only 21 trials (involving 75,785 women) contributed data.

However, more evidence of effect is needed, particularly for determining any adverse effects including placental abruption, premature

rupture of the membranes, neural tube defects and other congenital abnormalities, neurodevelopmental delay, very preterm births and

side-effects of the supplements.

B A C K G R O U N D

Description of the condition

Micronutrients are vitamins and minerals required in minute

amounts for normal functioning, growth and development.

Women in low-income countries often consume inadequate levels

of micronutrients due to limited intake of animal products, fruits,

vegetables and fortified foods (Huffman 1998). The resulting mi-

cronutrient deficiencies are exacerbated in pregnancy leading to

potentially adverse effects on the mother such as anaemia, hyper-

tension, complications of labour and even death (Ramakrishnan

1999). At least 50 million pregnant women in low-income coun-

tries are anaemic, primarily due to iron deficiency (Stoltzfus 1995).

Vitamin A deficiency affects millions of women and children

worldwide. A study carried out in Nepal showed that 20% of

pregnant women and 27% of postpartum women were vitamin

A deficient (West 1997). Approximately 100 million women of

reproductive age suffer from iodine deficiency (Leslie 1991). An

estimated 82%of pregnant womenworldwide have inadequate in-



takes of zinc to meet the normative needs of pregnancy (Caulfield

1998). In Egypt, suboptimal vitamin B6 status has been observed

among more than one-third of breastfeeding women based on

lowbreastmilk concentrations (Kirksey 1994). Low serum vitamin

B12 has been observed among pregnant and lactating women in

Mexico, and low breastmilk vitamin B12 was reported in Kenya

(Allen 1993).

Micronutrient status plays an important role in pregnancy and

birth outcomes. Iron deficiency results in anaemia, which may

increase the risk of death from haemorrhage after delivery al-

though its effects on fetal development and birth outcomes are still

unclear. Folic acid deficiency can lead to haematological conse-

quences, pregnancy complications and congenital malformations

but, again, the association with other birth outcomes is equivocal

(Black 2001). A clinical trial by Botto et al has demonstrated a pro-

tective effect of multivitamin supplements and folic acid against

neural tube defects and other defects such as orofacial clefts and

some heart defects, although the evidence is not as consistent or

as strong as with neural tube defects (Botto 2002). This was fur-

ther investigated by Lumley et al and periconceptional folate sup-

plementation was found to have a strong protective effect against

neural tube defects (De-Regil 2010).

Severe iodine deficiency results in pregnancy loss, mental retarda-

tion and cretinism (Dunn 1993) but little is known for other out-

comes, especially with marginal iodine deficiency (Ramakrishnan

1999). Deficiencies of other minerals such as magnesium, sele-

nium, copper and calcium have also been associated with com-

plications of pregnancy, childbirth or fetal development (Black

2001). Magnesium deficiency especially has been linked with pre-

eclampsia and preterm delivery (Chein 1996).

Vitamin A deficiency in pregnancy is known to result in night

blindness, to increase the risk of maternal mortality, and is asso-

ciated with premature birth, intrauterine growth retardation, low

birthweight and abruptio placentae (Ladipo 2000). A study from

Nepal (West 1999) showed that weekly vitamin A supplementa-

tion reduced maternal mortality by 40%. West et al in 1997 (West

1997) showed thatmaternalmortality inNepal decreased by about

half in women who received vitamin A for at least three months

before and during pregnancy (UNICEF 1998; West 1997). It was

also found that the prevalence of iron-deficiency anaemia in preg-

nancy was reduced from 76% in controls to 69% among those

receiving vitamin A (Stoltzfus 1997).

Zinc deficiency has been associated with complications of preg-

nancy and delivery such as pre-eclampsia and premature rupture

of membranes in some but not all studies (Caulfield 1998), as well

as with growth retardation, congenital abnormalities and retarded

neurobehavioural and immunological development in the fetus

(Black 2001). Ramakrishnan 1999 states that there is strong evi-

dence, primarily from high-income countries, that zinc, calcium

andmagnesium supplementation could improve birthweight, pre-

maturity and hypertension particularly in high-risk groups. Im-

proving maternal iron intake during pregnancy has been shown

in Peru to improve the iron status of newborns (OBrien 2003).

Description of the intervention

In 1999, the United Nations Childrens Fund (UNICEF), United

Nations University (UNU) and World Health Organization

(WHO) agreed on the composition of a proposed multiple-mi-

cronutrient tablet providing one recommended daily allowance of

vitamin A, vitamin B1, vitamin B2, niacin, vitamin B6, vitamin

B12, folic acid, vitamin C, vitaminD, vitamin E, copper, selenium

and iodine with 30 mg of iron and 15 mg of zinc for pregnant

women. However, according to the guidelines provided by theNa-

tional Research Council in 1989, 15 mg of zinc for pregnant and

lactating women is based on a dietary availability of zinc of ap-

proximately 20%. If dietary availability is only 10%, as is the case

in many low-income to middle-income countries, the nutritional

requirements of zinc might be much higher.

When multiple supplements were provided to HIV-positive preg-

nant women in Tanzania, the risk of low birthweight decreased by

44% and preterm births by 39% (Fawzi 1998). There is a pub-

lished review assessing the effect ofmicronutrient supplementation

in HIV-infected children and adults (Irlam 2010). In pregnant

women in Indonesia, daily supplements of vitaminA (retinol) with

iron (elemental iron) increased haemoglobin and had a greater im-

pact on reducing anaemia than iron alone (Suharno 1992; Suharno

1993). While absorption of both zinc and iron are inhibited when

combined (OBrien 2003), improvements in both iron and zinc

status were found among pregnant women receiving supplements

in Peru (Caulfield 1997). It was shown by Scholl that the risk of

low birthweight was reduced approximately two-fold with mul-

tivitamin supplement use during the first and second trimester

of pregnancy, although it appeared that this effect was due to an

associated two-fold reduction in the risk of preterm delivery. On

the other hand, a large Hungarian trial of micronutrient supple-

mentation (Czeizel 1996) found no significant effect on the rate

of fetal deaths, low birthweight and preterm births in singletons.

How the intervention might work

Some authors have questioned the effectiveness of multiple-mi-

cronutrient supplements due to possible interactions among nutri-

ents that can result in their impaired absorption (Argiratos 1994).

Studies have shown that high doses of iron impair the absorption

of zinc, and vice versa. The risk of interaction is larger when the

nutrients are provided as supplements (Sandstrom 2001). Man-

ganese affects iron absorption in a way that indicates that the intes-

tine cannot differentiate between manganese and iron (Rossander

1991). Similarly, high-dose zinc supplements (50 mg per day for

10weeks) reduce indices for iron and copper status (Yadrick 1989).

Calcium was shown to have a negative effect on iron absorption

(Hallberg 1991).



Vitamin C is a strong promoter of dietary iron absorption

(Hallberg 1986). However, long-term vitamin C supplementation

may impair the absorption of copper and thereby counteract the

positive effect on iron absorption. These effects of vitamin C on

copper are not conclusive (Jacob 1987). Vitamin C affects sele-

nium availability both positively and negatively depending on the

chemical form and dietary conditions (Lavender 1987).

Recent studies suggest that vitamin A and beta-carotene can en-

hance non-haemal iron absorption. Another issue is that frequen-

cies of supplementation and dose levels may not be compati-

ble (Mason 2001). Supplements may result in excess levels and

cause harm; for example, high doses of vitamin A in pregnant

women increases the risk of teratogenicity. An excess of vitamin E

in adult humans (Bell 1989) causes impaired leukocyte function,

increased bleeding, inhibition of platelet prostaglandin synthesis

and of platelet aggregation. Iron deficiency as well as iron overload

seem to involve a degree of oxidative stress. A vitamin C excess

has been reported to cause serious cardiovascular disturbances in

iron-overloaded patients (McLaran 1982). High doses of vitamin

C (500 mg per day) plus iron can cause certain oxidative base

modifications in DNA extracted from leucocytes of healthy hu-

man donors (Rehman 1998), however the significance of this is

unknown.

Authors argue that a poor pregnancy outcome is the result of a

multiplicity of factors and cannot be corrected by a narrow phar-

maceutical shortcut; instead, they call for an overall improvement

in antenatal care and dietary diversification (Gopalan 2002). The

effectiveness of already existing worldwide conventional iron or

folate supplementation programs for pregnant women has been

questioned (Yip 1996). These programs suffer from limited cov-

erage and poor compliance, and their limitation to the duration

of the pregnancy provides an insufficient time period in which to

reduce iron deficiency.

Why it is important to do this review

Multiple-micronutrient deficiencies often coexist and there is an

increased interest in evaluating the benefit of multiple-micronu-

trient supplements in pregnancy. Consideration that there may be

multiple deficiencies in the populations of low-income to middle-

income countries and that it is difficult to evaluate the effects of all

of the potentially important micronutrients, as well as their possi-

ble interactions, have lead some to conclude that a multivitamin

mineral supplement should be given during pregnancy (UNICEF

1999).

Combining multiple micronutrients in a single delivery mecha-

nism has been suggested as a cost-effective way to achievemultiple

benefits (Alnwick 1998; Yip 1997).Moreover, micronutrient defi-

ciencies are known to interact and a greater effect may be achieved

by multiple supplementation rather than single nutrient supple-

mentation. Clearly, substantial evidence is required before mul-

tiple-micronutrient supplementation programs are implemented

on a global scale (Bhutta 2009b). In this review we are looking at

supplementation with three or more micronutrients. Other rele-

vant information can be found in the trials conducted on individ-

ual vitamins and minerals and their effects.

O B J E C T I V E S

To evaluate the benefits to both mother and infant of multiple-

micronutrient supplements in pregnancy and to assess the risk of

adverse events as a result of supplementation.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All prospective randomised controlled trials evaluating multiple-

micronutrient supplementation during pregnancy and its effects

on the pregnancy outcome, irrespective of language or publica-

tion status of the trials. We included cluster-randomised trials but

quasi-randomised trials were excluded.

Types of participants

Pregnant women. There was no limit on the length of gestation

at the time of enrolment in the study. HIV-positive women were

excluded from the review.

Types of interventions

Studies comparing the outcomes of providing pregnant women

with multiple-micronutrient supplements containing three or

more micronutrients compared with placebo, no supplementa-

tion, or supplementation with two or lessmicronutrients. We eval-

uated the effects of micronutrients that were different in the two

groups and not any co-interventions. We compared multiple-mi-

cronutrient supplements containing at least three micronutrients

with supplements with two or less, or none, as iron with folic

acid or folic acid alone are standard recommendations for preg-

nant women in many countries. Trials that used fewer than three

supplements in the intervention group were excluded regardless

of their outcome. There were no limits on the duration of supple-

mentation. Since WHO recommends use of iron folic acid sup-

plementation in women during pregnancy as a part of routine an-

tenatal care, we also evaluated the effect of multiple-micronutrient

supplementation versus supplementation with iron and folic acid.



Types of outcome measures

Primary outcomes

1. Preterm births (births before 37 weeks of gestation)

2. Small-for-gestational age (as defined by the authors of the

trials)

3. Low birthweight (birthweight less than 2500 grams)

4. Premature rupture of membranes

5. Pre-eclampsia

6. Miscarriage (loss of pregnancy before 28 weeks of gestation)

7. Maternal mortality

8. Perinatal mortality

9. Stillbirths

10. Neonatal mortality

Secondary outcomes

1. Maternal anaemia

2. Neurodevelopmental delay (assessed using Bayley Scale of

Infant Development at six and 12 months of age)

3. Placental abruption

4. Very preterm births (births before 34 weeks of gestation)

5. Cost of supplementation

6. Side-effects of supplements

7. Congenital anomalies (including neural tube defects)

8. Maternal well being or satisfaction

9. Nutritional status of children (stunting, wasting and

underweight at 6, 12 and 24 months of age)

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Groups

Trials Register by contacting the Trials Search Co-ordinator (17

February 2012).

The Cochrane Pregnancy and Childbirth Groups Trials Register

is maintained by the Trials Search Co-ordinator and contains trials

identified from:

1. quarterly searches of the Cochrane Central Register of

Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of EMBASE;

4. handsearches of 30 journals and the proceedings of major

conferences;

5. weekly current awareness alerts for a further 44 journals

plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and

EMBASE, the list of handsearched journals and conference pro-

ceedings, and the list of journals reviewed via the current aware-

ness service can be found in the Specialized Register section

within the editorial information about the Cochrane Pregnancy

and Childbirth Group.

Trials identified through the searching activities described above

are each assigned to a review topic (or topics). The Trials Search

Co-ordinator searches the register for each review using the topic

list rather than keywords.

Searching other resources

We searched reference lists of retrieved articles and key reviews.

We contacted experts in the field for additional and ongoing trials.

We did not apply any language restrictions.

Data collection and analysis

For the methods used when assessing the trials identified in the

previous version of this review, see Appendix 1. For this update we

used the following methods when assessing the trials identified by

the updated search.

Selection of studies

The review authors independently assessed for inclusion all po-

tential studies that were identified as a result of the search strategy.

We resolved any disagreement through discussion.

Data extraction and management

We designed a form to extract data. For eligible studies, the review

authors extracted the data using the agreed form. We resolved

discrepancies through discussion. Data were entered into Review

Manager software (RevMan 2011) and checked for accuracy.

When information regarding any of the above was unclear, we

attempted to contact authors of the original reports to obtain

further details.

Assessment of risk of bias in included studies

The review authors independently assessed risk of bias for each

study using the criteria outlined in theCochrane Handbook for Sys-

tematic Reviews of Interventions (Higgins 2011). Any disagreement

was resolved by discussion.

(1) Random sequence generation (checking for possible

selection bias)

We described for each included study the method used to generate

the allocation sequence in sufficient detail to allow an assessment

of whether it should produce comparable groups.

We assessed the method as:

low risk of bias (any truly random process, e.g. random

number table; computer random number generator);



high risk of bias (any non-random process, e.g. odd or even

date of birth; hospital or clinic record number); or

unclear risk of bias.

(2) Allocation concealment (checking for possible selection

bias)

We described for each included study the methods used to con-

ceal allocation to interventions prior to assignment and to assess

whether intervention allocation could have been foreseen in ad-

vance of, or during recruitment, or changed after assignment.

We assessed the methods as:

low risk of bias (e.g. telephone or central randomisation;

consecutively numbered sealed opaque envelopes);

high risk of bias (open random allocation; unsealed or non-

opaque envelopes, alternation; date of birth);


(3) Blinding of participants, personnel and outcome

assessors (checking for possible performance bias)

We described for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which

intervention a participant received. We considered studies to be

at low risk of bias if they were blinded, or if we judged that the

lack of blinding would be unlikely to affect results. We assessed

blinding separately for different outcomes or classes of outcomes.


low, high or unclear risk of bias for participants;

low, high or unclear risk of bias for personnel;

low, high or unclear risk of bias for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition

bias due to the amount, nature and handling of incomplete

outcome data)

We described for each included study, and for each outcome or

class of outcomes, the completeness of data including attrition

and exclusions from the analysis. We state whether attrition and

exclusions were reported and the numbers included in the analysis

at each stage (compared with the total number of randomised

participants), reasons for attrition or exclusion where reported,

and whether missing data were balanced across groups or were

related to outcomes. Where sufficient information is reported, or

was supplied by the trial authors, we re-include missing data in

the analyses which we undertook.

We assessed methods as:

low risk of bias (e.g. no missing outcome data; missing

outcome data balanced across groups);

high risk of bias (e.g. numbers or reasons for missing data

imbalanced across groups; as treated analysis done with

substantial departure of the intervention received from that

assigned at randomisation);


(5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated the

possibility of selective outcome reporting bias and what we found.


low risk of bias (where it is clear that all of the studys

prespecified outcomes and all expected outcomes of interest to

the review have been reported);

high risk of bias (where not all the studys prespecified

outcomes have been reported; one or more of the reported

primary outcomes were not prespecified; outcomes of interest are

reported incompletely and so cannot be used; study fails to

include results of a key outcome that would have been expected

to have been reported);


(6) Overall risk of bias

We made explicit judgements about whether studies are at high

risk of bias, according to the criteria given in the Handbook for

Systematic Reviews of Interventions (Higgins 2011). With reference

to (1) to (6) above, we assessed the likely magnitude and direction

of the bias and whether we considered it was likely to impact on

the findings. We explored the impact of the level of bias through

undertaking Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio

with 95% confidence interval.

Continuous data

For continuous data, we used mean difference when outcomes

were measured in the same way between trials.

Unit of analysis issues

Cluster-randomised trials

There were six cluster-randomised trials included in this review

(Bhutta 2009a;Christian 2003; SUMMIT2008; Sunawang 2009;

Zagre 2007; Zeng 2008). We used the generic inverse variance

method to include cluster-randomised trials.We adjusted the stan-

dard errors of their estimates using the methods described in the

Handbook, using an estimate of the intracluster correlation co-effi-

cient (ICC) derived from the trial (if possible), or we used cluster-



adjusted estimates. If we identified both cluster-randomised tri-

als and individually randomised trials, we synthesised the relevant

information. We considered it reasonable to combine the results

from both if there was little heterogeneity between the study de-

signs and the interaction between the effect of the intervention and

the choice of randomisation unit was considered to be unlikely.

Dealing with missing data

For included studies, we noted levels of attrition. We explored the

impact of including studies with high levels of missing data in the

overall assessment of treatment effect by using sensitivity analysis.

For all outcomes we carried out analyses, as far as possible, on an

intention-to-treat basis, that is we attempted to include all partic-

ipants randomised to each group in the analyses. All participants

were analysed in the group to which they were allocated, regardless

of whether or not they received the allocated intervention. The

denominator for each outcome in each trial was the number ran-

domised minus any participants whose outcomes were known to

be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using

the T, I and Chi statistics. We regarded heterogeneity as sub-

stantial if I was greater than 50% and either T was greater than

zero or there was a low P value (less than 0.10) in the Chi test for

heterogeneity.

Assessment of reporting biases

Where there were 10 or more studies in the meta-analysis we in-

vestigated reporting biases (such as publication bias) using funnel

plots. We assessed funnel plot asymmetry visually and proposed

formal tests for funnel plot asymmetry. As our dichotomous out-

comesmeasured effects of intervention as risk ratios, we used visual

assessment of funnel plots. If asymmetry was suggested by a visual

assessment, we performed exploratory analyses to investigate it.

For future review updates, we propose the test by Egger 1997.

Data synthesis

We analysed the data using Review Manager (RevMan 2011) and

generated risk ratios with 95% confidence intervals for the di-

chotomous outcomes. We used fixed-effect model meta-analysis

for combining data where trials were examining similar interven-

tions and the trials populations and methods were judged suffi-

ciently similar. Where we suspected methodological heterogeneity

between studies sufficient to suggest that treatment effects may

differ between trials, we used random-effects model meta-analysis.

Subgroup analysis and investigation of heterogeneity

Statistical heterogeneity among the trials was measured by visu-

ally inspecting the forest plots and calculating the T, I and Chi

statistics. Clinical heterogeneity was assessed for those outcomes

for which available the literature indicated the presence of clinical

diversity. We prespecified the following subgroup analyses to in-

vestigate statistical or clinical heterogeneity for primary outcomes:

1. gestational age at which the supplementation was initiated,

duration of supplementation;

2. dosage of the micronutrients in the supplement;

3. baseline nutritional status of the mother (including body

mass index (BMI), height and micronutrient levels).

Differences between subgroups were assessed by interaction tests

and the P values.

Sensitivity analysis

Sensitivity analysis was undertaken to study the effect of multiple-

micronutrient supplementation on various outcomes by exclud-

ing trials in which the method of randomisation, allocation con-

cealment or blinding was not achieved, or trials with a large loss

to follow up (greater than 20%).

R E S U L T S

Description of studies

See:Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

Results of the search

Twenty-three trials (involving 76,532 women) were identified as

eligible for inclusion in this review but only 21 trials (involving

75,785 women) contributed data to the review. Sixty-four trials

were excluded.Therewere six ongoing trials (Biggs 2011;Cogswell

2006; Dewey 2011; Fall 2007; Moore 2011; West 2011), see

Characteristics of ongoing studies for more information.

Included studies

A total of 23 trials (involving 76,532 women) were identified

as eligible for inclusion in this review. Of these, two studies

(Hininger 2004; Sood 1975) either did not report outcomes that

were of interest in this review or presented data in a format

that precluded their inclusion. Hence, these included studies did

not contribute data to the analyses. A total of 75,785 women

participated in the remaining 21 included trials (Bhutta 2009a;

Brough 2010; Christian 2003; Dieckmann 1943; Fawzi 2007;



Friis 2004; Gupta 2007; Jarvenpaa 2007; Kaestel 2005; Osrin

2005; Ramakrishnan 2003; Roberfroid 2008; Rumiris 2006;

SUMMIT 2008; Sunawang 2009; Tatala 2002; Theobald 1937;

Tofail 2008; Vadillo-Ortega 2011; Zagre 2007; Zeng 2008) of

which sixwere cluster-randomised (Bhutta 2009a;Christian 2003;

SUMMIT 2008; Sunawang 2009; Zagre 2007; Zeng 2008). Most

of the outcomes were defined in the same way across different trials

except for miscarriage, which was defined differently in one trial

(Dieckmann 1943) and hence did not allow inclusion of data from

this trial. Two trials used different cut-offs to define anaemia (Fawzi

2007; Zeng 2008). See the Characteristics of included studies table

for further details of included studies.

Participants

The 21 included trials contributing data to the analysis included

75,785 women at varying gestational stages, ranging from early

pregnancy to 36 weeks of gestation. Pregnant women with a hae-

moglobin of less than 80 g/L, with a serious medical condition

or a complication of pregnancy such as cardiac disease, pneumo-

nia and threatened abortion were not eligible for inclusion in the

trials. However, Vadillo-Ortega 2011 recruited women who were

at high risk for pre-eclampsia. One trial (Friis 2004) included a

subgroup of pregnant women who were HIV-1 infected but their

data have not been included in this review. Baseline characteris-

tics of the participants in the intervention and the control groups

were comparable in the included trials except for minor differences

in five trials (Christian 2003; Friis 2004; Ramakrishnan 2003;

Roberfroid 2008; Zagre 2007); and these characteristics were not

reported in one trial (Theobald 1937). In Friis 2004, a higher

proportion of primigravidae were found in the placebo group.

In Ramakrishnan 2003, there was a higher proportion of single

mothers and a lower mean BMI in the intervention group. In

Christian 2003, more participants in the control group belonged

to a specific ethnic background and owned land. In Roberfroid

2008, the haemoglobin level was lower in the intervention group

and the BMI was lower in the control group. In Zagre 2007, the

intervention group had more households and preventive measures

against malaria, whereas the placebo group had less education and

more poverty.

Intervention

Fourteen trials assessed multiple-micronutrient supplementation

versus supplementation with two or less micronutrients (Bhutta

2009a; Christian 2003; Dieckmann 1943; Fawzi 2007; Gupta

2007; Kaestel 2005;Osrin 2005; Ramakrishnan 2003; Roberfroid

2008; Rumiris 2006; SUMMIT 2008; Sunawang 2009; Tofail

2008; Zagre 2007; Zeng 2008). Another two trials had a compo-

nent of nutritional education along with supplementation (Bhutta

2009a; Zagre 2007) whereas four trials assessed multiple micronu-

trients against a placebo (Brough 2010; Friis 2004; Theobald

1937; Vadillo-Ortega 2011). Two included trials assessed the im-

pact of fortification with multiple micronutrients, Tatala 2002

used a fortified beverage mix and Jarvenpaa 2007 used fortified

mineral water. The composition of the multiple-micronutrient

supplement was different in all included trials. All supplements

were given orally to the pregnant women throughout pregnancy

from the time of enrolment. However, the duration of supple-

mentation varied because the time of enrolment differed across

the trials. Eight trials enrolled participants in the first trimester

of pregnancy (Brough 2010; Christian 2003; Dieckmann 1943;

Ramakrishnan 2003; Roberfroid 2008; Rumiris 2006; Tofail

2008; Zagre 2007). One trial enrolled participants with gesta-

tion of less than 28 weeks (Zeng 2008). Three trials enrolled

participants in the second trimester (Bhutta 2009a; Osrin 2005;

Sunawang 2009), three trials enrolled women in both second and

third trimester (Friis 2004; Gupta 2007; Vadillo-Ortega 2011),

whereas three trials enrolled pregnant women who were less than

37 weeks gestation (Fawzi 2007; Kaestel 2005; SUMMIT 2008).

Supplementation was given until delivery in 13 of the included

trials (Bhutta 2009a; Brough 2010; Dieckmann 1943; Friis 2004;

Gupta 2007; Kaestel 2005; Osrin 2005; Ramakrishnan 2003;

Rumiris 2006; Tofail 2008; Vadillo-Ortega 2011; Zagre 2007;

Zeng2008). Supplementation continueduntil fourweeks after de-

livery in one trial (Sunawang 2009), six weeks after delivery in the

Fawzi 2007 trial, 12 weeks after delivery in three trials (Christian

2003; Roberfroid 2008; SUMMIT 2008) and for five weeks after

a stillbirth or miscarriage (Christian 2003).

Excluded studies

Sixty trials were excluded from the review. Briefly, 33 trials eval-

uated the effects of a single or two micronutrients or compounds

(Beazley 2002; Bergmann 2006; Carrasco 1962; Caulfield 1999;

Caulfield 1999a;Chames 2002;Goldenberg 1995;Gopalan 2004;

Hillman 1963; Holly 1955; Hunt 1983; Hunt 1984; Hunt 1985;

Iannotti 2008; Lucia 2007; Ma 2008; Marya 1987; Mathan

1979; Merialdi 1999; Muslimatun 2001a; Muslimatun 2001b;

Ochoa-Brust 2007; Robertson 1991; Sachdeva 1993; Sagaonkar

2009; Schmidt 2001; Schmidt 2002; Semba 2000; Semba 2001;

Suharno 1993; Suprapto 2002; Tanumihardjo 2002; Zavaleta

2000), nine trials did not satisfy the study design criteria (Aguayo

2005; Biswas 1984; Kubik 2004; Kynast 1986; Menon 1962;

Park 1999; Peoples League 1946; Sun 2010; Thauvin 1992) and

three trials were in HIV-positive women (Fawzi 1998; Merchant

2005; Webb 2009) and hence were excluded from the review.

Czeizel 1996 and ICMR 2000 evaluated supplementation in the

periconceptional period; An 2001, Guldholt 1991, Graham 2007

and Fleming 1986 assessed different doses of micronutrients;

Feyi-Waboso 2005 evaluated parenteral infusion; Dawson 1987

and Dawson 1998 assessed the impact of supplementation with

more than 11 micronutrients; Ramirez-Velez 2011 compared nine

versus three micronutrients; and Ling 1996 evaluated a herbal



tonic; hence they were not found to be eligible. Four trials were ex-

cluded because they evaluated the acceptability of different forms

of supplementation such as powder, tablet or spread (Young 2010);

balanced energy protein supplementation (Huybregts 2009); or

polyunsaturated fatty acids fortification inmilk fortifiedwithmul-

tiple micronutrients (Mardones 2007). The cohort of an included

study (Tofail 2008) was later randomised to breastfeeding coun-

selling or standard care groups measuring impact on postnatal

growth in children (Kabir 2009) and was hence excluded.

See the Characteristics of excluded studies table for more details.

Risk of bias in included studies

The included trials were of variable methodological quality. Par-

ticipants were adequately randomised to the treatment groups in

15 trials (Bhutta 2009a; Christian 2003; Fawzi 2007; Friis 2004;

Gupta 2007; Kaestel 2005; Osrin 2005; Ramakrishnan 2003;

Roberfroid 2008; Rumiris 2006; Sood 1975; SUMMIT 2008;

Theobald 1937; Vadillo-Ortega 2011; Zeng 2008) whereas the

method used for generating the randomisation sequence was not

described in sufficient detail in the remaining studies to permit

judgement. Allocation of participants in to the intervention and

control groups was concealed in 10 trials (Bhutta 2009a; Fawzi

2007; Friis 2004; Gupta 2007; Osrin 2005; Ramakrishnan 2003;

Roberfroid 2008; SUMMIT 2008; Vadillo-Ortega 2011; Zeng

2008); it was unclear in 10 trials (Brough 2010; Christian 2003;

Dieckmann 1943;Hininger 2004; Jarvenpaa 2007; Rumiris 2006;

Sunawang 2009; Tatala 2002; Tofail 2008; Zagre 2007); whereas

allocation was not probably concealed in the remaining three trials

(Kaestel 2005; Sood 1975; Theobald 1937).

In two trials (Bhutta 2009a; Tofail 2008), the participants and

the outcome assessors were blinded to the treatment allocation.

Another 14 trials showed blinding of the participants, care-

givers and the outcome assessors (Brough 2010; Christian 2003;

Fawzi 2007; Friis 2004; Gupta 2007; Kaestel 2005; Osrin 2005;

Ramakrishnan 2003; Roberfroid 2008; Rumiris 2006; SUMMIT

2008; Vadillo-Ortega 2011; Zagre 2007; Zeng 2008). However,

Tatala 2002 showed blinding of participants and caregivers; and

Sunawang 2009 showed blinding of participants only. Jarvenpaa

2007 was a double blind trial but it was not clear as to who was

blinded; and blinding was not stated in the text of Dieckmann

1943.

Loss to follow up was less than 5% in two trials (Rumiris 2006;

Zeng 2008); between 5% to 9.9% in five trials (Christian 2003;

Fawzi 2007; Osrin 2005; Roberfroid 2008; SUMMIT 2008); and

between 10% to 19.9% in six trials (Bhutta 2009a; Brough 2010;

Sunawang 2009; Tatala 2002; Vadillo-Ortega 2011; Zagre 2007).

It was more than 20% in seven trials (Friis 2004; Gupta 2007;

Hininger 2004; Kaestel 2005; Ramakrishnan 2003; Sood 1975;

Tofail 2008); and not reported in three trials (Dieckmann 1943;

Jarvenpaa 2007; Theobald 1937). The method of randomisation

and allocation concealment was not stated in the text of one trial (

Dieckmann 1943). Intention-to-treat analysiswas used in all of the

trials. In this review, an intention-to-treat analysis was conducted

for all outcomemeasures. SeeFigure 1; Figure 2 andCharacteristics

of included studies table for further details on the methodological

quality of the included studies.

Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as

percentages across all included studies.



Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included

study.



Effects of interventions

Primary outcome

1. Multiple micronutrients versus controls (no supplements,

placebo or two or less than two micronutrients)

When compared with supplementation of two or less micronu-

trients, no supplementation or a placebo, multiple-micronutrient

supplementation resulted in a statistically significant decrease in

the number of low birthweight (LBW) infants (risk ratio (RR)

0.86; 95% confidence interval (CI) 0.80 to 0.91; 15 studies;

Analysis 1.6) and small-for-gestational age (SGA) babies (RR0.87;

95% CI 0.83 to 0.92; 15 studies; Analysis 1.2). No statistically

significant differences were shown for the outcomes of preterm

birth (RR 0.99; 95% CI 0.97 to 1.02; 17 studies; Analysis 1.1),

miscarriage (RR 0.90; 95%CI 0.79 to 1.02; eight studies; Analysis

1.11), pre-eclampsia (RR 0.47; 95% CI 0.22 to 1.03; four stud-

ies; Analysis 1.10), maternal mortality (RR 0.97; 95% CI 0.63 to

1.48; three studies; Analysis 1.12), perinatal mortality (RR 0.96;

95% CI 0.84 to 1.10; 12 studies; Analysis 1.13), stillbirths (RR

0.95; 95% CI 0.85 to 1.06; 13 studies; Analysis 1.14) and neona-

tal mortality (RR 1.01; 95% CI 0.89 to 1.16; 10 studies; Analysis

1.15).

Subgroup analysis

We performed subgroup analyses to assess the effect of clinical

diversity of participants on SGA and LBW. For SGA, the pooled

effect of multiplemicronutrients was more pronounced for studies

with women having a mean BMI at least 20 kg/m (RR 0.85; 95%

CI 0.80 to 0.91; 11 studies; Analysis 1.3) as compared to studies

of women with a mean BMI less than 20 kg/m (RR 0.90; 95%

CI 0.83 to 0.98), however the difference between subgroups was

not statistically significant (P = 0.31). Similar effects were noted

for a mean maternal height at least 154.9 cm (RR 0.82; 95% CI

0.76 to 0.89; seven studies; Analysis 1.4) as compared to a mean

maternal height less than 154.9 cm (RR 0.91; 95% CI 0.85 to

0.98; eight studies; Analysis 1.4) (P = 0.07); and the duration of

supplementation and gestational week at which supplementation

was initiated (after 20 weeks RR 0.83; 95% CI 0.76 to 0.91 versus

before 20 weeks RR 0.90; 95%CI 0.84 to 0.96; P = 0.22; Analysis

1.5). The effects of multiple micronutrients on LBW in various

subgroupswere also similar:meanBMI less than20kg/m (average

RR 0.78; 95% CI 0.65 to 0.93; four studies; random-effects, T2

= 0.02, I2 = 60%) versus mean BMI at least 20 kg/m (RR 0.88;

95% CI 0.81 to 0.96; 10 studies) (P = 0.20; Analysis 1.7); mean

maternal height less than 154.9 cm (average RR 0.86; 95% CI

0.76 to 0.98; eight studies; random-effects, T2= 0.02, I2= 53%)

versus maternal height at least 154.9 cm (RR 0.86; 95% CI 0.77

to 0.95; seven studies) (P = 0.93, Analysis 1.8); and gestational

week at which supplementation was initiated before 20 weeks (RR

0.88; 95% CI 0.81 to 0.95; 10 studies) versus after 20 weeks (RR

0.82; 95% CI 0.75 to 0.91; 5 studies) (P = 0.31, Analysis 1.9).

2. Multiple micronutrients versus iron folate only

When multiple-micronutrient supplementation was compared

with iron and folic acid supplementation, the effect on the out-

comes SGA (RR 0.87; 95% CI 0.81 to 0.95; 14 studies; Analysis

2.2) and LBW(RR0.89; 95%CI 0.83 to 0.94; 14 studies; Analysis

2.6) remained significant. Non-significant differences were shown

for the other primary outcomes: preterm births (RR 0.99; 95%CI

0.96 to 1.02; 15 studies; Analysis 2.1), miscarriage (RR 0.90; 95%

CI 0.79 to 1.02; eight studies; Analysis 2.11), maternal mortality

(RR 0.97; 95% CI 0.63 to 1.48; three studies; Analysis 2.12);

and perinatal mortality (average RR 0.99; 95% CI 0.84 to 1.16;

11 studies; random-effects, T2 = 0.03, I2 = 56%; Analysis 2.13),

stillbirths (RR 0.96; 95% CI 0.86 to 1.07; 13 studies; Analysis

2.17) and neonatal mortality (RR 1.01; 95% CI 0.89 to 1.15;

nine studies; Analysis 2.18).

Subgroup analysis

The effect of multiple-micronutrient supplementation as com-

pared to iron and folic acid on the outcomes of SGA and LBW

were also evaluated in various prespecified subgroups. Subgroup

analysis based on mean maternal BMI showed that the effect of

multiple micronutrients on SGA as compared to iron and folic

acid was significant for women with mean BMI at least 20 kg/

m (RR 0.85; 95% CI 0.79 to 0.91; 10 studies) whereas it was

non-significant for women with mean BMI less than 20 kg/m

(average RR 0.86; 95% CI 0.69 to 1.08; four studies; random-

effects, T2 = 0.03, I2 = 65%) (P = 0.91; Analysis 2.3). Similar

effects were observed for subgroups according to maternal height:

meanmaternal height at least 154.9 cm (RR 0.82; 95%CI 0.76 to

0.89; six studies) and less than 154.9 cm (RR 0.97; 95% CI 0.90

to 1.04) (P = 0.004; Analysis 2.4); and gestation week at which

supplementation was initiated: after 20 weeks (RR 0.83; 95% CI

0.76 to 0.91; five studies) and before 20 weeks (RR 0.94; 95%

CI 0.88 to 1.01; nine studies) (P = 0.04; Analysis 2.5). Effects of

intervention on LBW for various subgroups were as follows: BMI

less than 20 kg/m (average RR 0.80; 95% CI 0.62 to 1.02; four

studies; random-effects, T2 = 0.05, I2 = 79%) and BMI at least

20 kg/m (RR 0.88; 95% CI 0.81 to 0.96; 10 studies) (P = 0.44;

Analysis 2.7); maternal height less than 154.9 cm (average RR

0.90; 95% CI 0.77 to 1.04; eight studies; random-effects, T2 =

0.03, I2 = 63%) and maternal height at least 154.9 cm (RR 0.85;



95% CI 0.76 to 0.94; six studies) (P = 0.56; Analysis 2.8); and

gestational week at initiation of supplementation before 20 weeks

(RR 0.93; 95% CI 0.86 to 1.02; nine studies) and after 20 weeks

(RR 0.82; 95% CI 0.75 to 0.91; five studies) (P = 0.05; Analysis

2.9).

The results for perinatal mortality were found to be heterogeneous

(Chi = 22.47, df = 10, P = 0.01; I = 56%). Heterogeneity was

investigated using subgroup analyses: BMI less than 20 kg/m (RR

1.19; 95%CI 0.94 to 1.50; three trials) and BMI at least 20 kg/m

(average RR 0.93; 95% CI 0.78 to 1.11; eight studies; random-

effects, T2 = 0.03, I2 = 56%) (P = 0.10; Analysis 2.14); maternal

height less than 154.9 cm (RR 0.95; 95% CI 0.77 to 1.17; seven

studies) and maternal height at least 154.9 cm (average RR 1.08;

95%CI 0.79 to 1.50; four studies; random-effects, T2 = 0.07, I2 =

71%) (P = 0.49; Analysis 2.15); and gestational week at initiation

of supplementation before 20 weeks (average RR 1.09; 95% CI

0.84 to 1.42; eight studies; random-effects, T2 = 0.08, I2 = 57%)

and after 20 weeks (RR 0.88; 95% CI 0.80 to 0.97; three studies)

(P = 0.14; Analysis 2.16).

Analyses for the outcomes of preterm birth, LBW, SGA, stillbirths

and perinatal mortality contained more than 10 studies (range 12

to 16). Funnel plots for the assessment of reporting bias did not

reveal any substantial asymmetry (Figure 3; Figure 4; Figure 5;

Figure 6; Figure 7).

Figure 3. Funnel plot of comparison: 1 Multiple micronutrients versus controls (no supplements, placebo or

two or less than two micronutrients), outcome: 1.1 Preterm births.




two or less than two micronutrients), outcome: 1.2 Small-for-gestational age.




two or less than two micronutrients), outcome: 1.6 Low birthweight.




two or less than two micronutrients), outcome: 1.13 Perinatal mortality.




two or less than two micronutrients), outcome: 1.14 Stillbirths.

Our review found only two trials of fortification with multiple

micronutrients (Jarvenpaa 2007; Tatala 2002) and hence the in-

dependent effect of studies utilising a fortification strategy could

not be evaluated. No trial measured effects on premature rupture

of membranes.

Secondary outcomes

Multiple-micronutrient supplementation when compared with

supplementation of two or less micronutrients, no supplementa-

tion or a placebo showed a statistically significant decrease in ma-

ternal anaemia in the third trimester (average RR 0.81; 95% CI

0.66 to 0.98; eight trials; random-effects, T2 = 0.05, I2 = 70%;

Analysis 1.16). However, the result was not significant when mul-

tiple micronutrients were compared with iron and folic acid (RR

0.96; 95% CI 0.86 to 1.07; six trials; Analysis 2.19).

A number of prespecified clinically important outcomes could not

be assessed due to insufficient data from the included trials. These

included the followingoutcomes, whichweremeasured either only

in one trial or in none: placental abruption (Dieckmann 1943),

congenital anomalies including neural tube defects (Osrin 2005),

side-effects of multiple-micronutrient supplementation (Gupta

2007), neurodevelopmental delay (Zeng 2008), cost of supple-

mentation, maternal well being or satisfaction, and nutritional sta-

tus of the children.

Sensitivity analysis

Sensitivity analysis was undertaken to study the effect of multiple-

micronutrient supplementation on various outcomes by excluding

trials in which the methods of randomisation, allocation conceal-

ment and blinding were not stated in the text (Dieckmann 1943).

However, the overall effect estimate and the CI were not sensitive

to this change. Similarly, trials with losses to follow up of more

than 20% were excluded (Friis 2004; Gupta 2007; Kaestel 2005;

Ramakrishnan 2003; Tofail 2008) from the analyses of LBW and

SGA and this exclusion did not affect the estimates.

D I S C U S S I O N

This updated review is now comprised of Twenty-three included

studies (involving 76,532 women) but only 21 trials (involving

75,785 women) contributed data towards our analyses.



Whether to use a multiple-micronutrient supplement or iron fo-

late or no supplements during pregnancy is a very important clini-

cal question due to its effects on the fetus and themother. This up-

dated reviewhas incorporated a further 13 recent studies. From the

22 included studies, 12 studies used the multiple-micronutrient

supplement UNIMAPP formulation by UNICEF and six studies

used other combinations of these micronutrients. Overall, mul-

tiple-micronutrient supplementation showed a significant effect

on small-for-gestational age (SGA) and low birthweight (LBW)

outcomes when compared to supplementation with two or less

micronutrients, no supplementation or a placebo. Comparison of

the multiple-micronutrient supplementation with iron and folate

showed similar beneficial effects on SGA and LBW outcomes.

These findings corroborate those of recent systematic reviews, the

review commissionedbyUNICEF/WHO/SCNof 12UNIMAPP

trials (Fall 2009; Margetts 2009) and a systematic review using

Child Health Epidemiology Reference Group (CHERG) rules for

the Lives Saved Tool (LiST) (Haider 2011).

Multiple micronutrients were found to reduce the SGA births by

10% and LBW babies by 11% as compared to iron folate sup-

plements. They failed to show a significant impact on any of the

other outcomes of pregnancy. One of the postulated pathways for

the significant impact on these two outcomes is through an in-

crease in birthweight, with higher birthweight resulting in a lower

proportion of LBW babies and also reducing the proportion of

SGA births. This is supported by the evidence of an impact on

birthweight in the supplemented group as compared to iron and

folic acid in most of the included studies wherein the major pro-

portion of pregnant women were taking supplements in the third

trimester, which is a period of significant increase in fetal weight.

Among the included studies, several studies recruited pregnant

women in the first trimester with supplementation starting from

the second trimester; whereas the other trials recruited almost 80%

of their participants by the end of the second trimester, and with

only two trials (Friis 2004; Gupta 2007) recruiting after 22 or 24

months of gestation. This further supports the postulated path-

way as the intervention was in place much before the beginning of

third trimester, a possible window of opportunity to improve fetal

weight. Furthermore, the significant effect does not seem to be the

result of increasing the duration of gestation as multiple micronu-

trients failed to have a significant impact on preterm births.

Most of the studies included in this review were undertaken in de-

veloping countrieswith high fertility rates, lowmaternal bodymass

index (BMI), a high prevalence of iron deficiency anaemia, and fre-

quent subclinical micronutrient deficiencies (Bhutta 2008). Stud-

ies have shown that a significant proportion of pregnant women

suffer from multiple micronutrient deficiencies at the same time.

These have been associated with poor pregnancy outcomes includ-

ing LBW (Allen 2005; Keen 2003). Anaemia, especially as a result

of iron deficiency which is frequent in these women, is also possi-

bly associated with an increased risk of infections (Oppenheimer

2001). Whilst the objective of the review was not to measure im-

pact on the immune status or maternal infections, our findings of

a significant impact on LBW and SGA births as a result of multi-

ple-micronutrients supplementation could be through improved

nutritional status and hence better immune system and resistance

to maternal infections.

Maternal anthropometry prepregnancy and weight gain during

pregnancy have also been implicated in various neonatal and child

outcomes. Maternal height seems to be a stable and easily measur-

able variable in the setting of developing countries. Reviews have

identified short maternal stature as an important determinant of

intrauterine growth retardation and LBW (Kramer 2003; WHO

1995). Short maternal stature (short height) has been found to

be significantly associated with an increased risk of child mortal-

ity, underweight infants and stunting (Ozaltin 2010; Voigt 2010).

Our subgroup analyses indicate thatmultiplemicronutrients failed

to show a significant effect on the SGA outcome in women with

poor nutritional status at baseline, defined as maternal height less

than 154.9 cm and BMI less than 20 kg/m. Multiple micronu-

trients showed an 18% reduction in SGA babies among women

with a meanmaternal height at least 154.9 cm as compared to iron

folate, whereas the effect was found to be non-significant among

women with a mean height less than 154.9 cm. Similarly,multiple

micronutrients showed a 15% reduction in SGA babies among

women with a mean BMI at least 20 kg/m whereas the effect was

non-significant among those women with a mean BMI less than

20 kg/m. These findings should be interpreted with caution but

suggest a possible role of multiple micronutrients in preventing

poor pregnancy outcomes but only in women with good nutri-

tional status at baseline, and an absence of similar effects in women

with poor nutritional status at the time of conception. This fur-

ther highlights the contribution of maternal malnutrition to poor

fetal anthropometry and stunting later in childhood, resulting in

an intergenerational transfer of malnutrition.

We failed to find a significant effect of the multiple micronutri-

ents on the outcomes of perinatal mortality, stillbirths and neona-

tal mortality. Our earlier review, which included data from nine

studies, had also failed to show an impact on these pregnancy

outcomes. These findings corroborate those from recent reviews

(Haider 2011; Ronsmans 2009). It can be hypothesised that a re-

duction in fetal growth restriction and SGA babies may contribute

indirectly to improved infant survival. Recent reviews indicate that

poor fetal growth results in a higher risk of neonatal mortality

through neonatal infections such as sepsis, diarrhoea and pneu-

monia; and through birth asphyxia (Black 2008). This review up-

date did not find a significant effect of multiple micronutrients on

neonatal mortality. It is important to note that of the studies con-

ducted so far, only the Indonesian SUMMIT trial was sufficiently

powered to evaluate an effect on early infant mortality (SUMMIT

2008). There is controversy regarding the possible harmful effect

of multiple-micronutrient supplements by increasing the risk of



perinatal and neonatal mortality through increased birth asphyxia

in heavier babies (Christian 2005). Two trials conducted in Nepal

by Christian et al and Osrin et al both found a non-significant

increase in the risk of neonatal and perinatal mortality, but their

pooled effect estimate showed a significant increase in the risk of

these outcomes (Christian 2003; Osrin 2005). However, this con-

cern has been questioned by other researchers in the field and has

not been observed in other studies (Bhutta 2009b;Huffman 2005;

Shrimpton 2005). The multiple-micronutrient supplementation

review using CHERG methodology also found no significant in-

crease in the risk of neonatal mortality as a result of this interven-

tion. The increased risk may be related to the absence of skilled

care at delivery and the standard of care in the health systems.

This is also supported by the finding of a significant increase in

the subgroup of populations where the majority of births occurred

at home, and no effect where skilled birth care was available and

the majority of births took place in facilities (Haider 2011).

As noted earlier, the composition of the multiple-micronutrient

supplements was different in all included trials (Table 1), and use

of folic acid alone or iron with folic acid is a standard recommen-

dation for pregnant women in many countries globally. In order

to identify the effect of a micronutrient on pregnancy outcomes

and to justify its inclusion in routine antenatal care, eachmicronu-

trient should be evaluated against a placebo in women receiving

iron with folic acid. This can especially prove useful for countries

or regions with deficiencies of single micronutrients.

A U T H O R S C O N C L U S I O N SImplications for practice

Whilst multiple micronutrients have been found to have a signifi-

cant impact on small-for-gestational age and low birthweight out-

comes, more evidence is needed to guide a universal policy change

and to suggest replacement of routine iron and folate supplemen-

tation with a multiple-micronutrient supplement. There is also

insufficient evidence regarding adverse effects and to make any

conclusions that multiple-micronutrient supplementation during

pregnancy is harmful to the mother or the fetus.

Implications for research

Further trials with larger sample sizes are needed to evaluate ef-

fects on mortality and other morbidity outcomes. Trials that are

adequately powered to evaluate effects on mortality outcomes are

needed urgently. Trials should assess the effect of variability be-

tween different combinations and dosages, keeping within the safe

recommended levels. Additionally, data should be collected on

outcomes which would allow an assessment of the risk of excess

supplementation, potential adverse interactions between the mi-

cronutrients, and the other outcomes that we failed to assess in

this review.

A C K N OW L E D G E M E N T S

This reviewwas prepared inpart during the FellowshipProgramme

organised by theCochrane Infectious Diseases Group in July 2003

andMarch 2005.TheDepartment for InternationalDevelopment

(UK) supports this programme through the Effective Health Care

Research ProgrammeConsortiumat the LiverpoolTropical School

of Medicine. The views expressed are not necessarily those of the

Department for International Development.

We would like to thankMs LynnHampson for her assistance with

the literature search, and Professor James Neilson who provided

support and guidance for the review.

As part of the prepublication editorial process, this review has been

commented on by three peers (an editor and two referees who are

external to the editorial team) and the Groups Statistical Adviser.

R E F E R E N C E S

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Brough 2010 {published data only}

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EK. Effect of multiple-micronutrient supplementation on

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Christian 2003 {published data only}

Christian P, Darmstadt GL, Wu L, Khatry SK, LeClerq

SC, Katz J, et al.The effect of maternal micronutrient

supplementation on early neonatal morbidity in rural

Nepal: a randomised, controlled, community trial. Archives

of Disease in Childhood 2008;93(8):6604.

Christian P, Jiang T, Khatry SK, LeClerq SC, Shrestha SR,

West Jr KP. Antenatal supplementation with micronutrients



and biochemical indicators of status and subclinical

infection in rural Nepal. American Journal of Clinical

Nutrition 2006;83:78894. Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq

SC, Shrestha SR, et al.Effects of alternative maternal

micronutrient supplements on low birth weight in rural

Nepal: double blind randomised community trial. BMJ

2003;326:571.

Christian P, Khatry SK, LeClerq SC, Dali SM. Effects of

prenatal micronutrient supplementation on complications

of labor and delivery and puerperal morbidity in rural

Nepal. International Journal of Gynaecology and Obstetrics

2009;106(1):37.

Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer

BA, Cole PM, et al.Prenatal micronutrient supplementation

and intellectual and motor function in early school-aged

children in Nepal. JAMA 2010;304(24):271623.

Christian P, Shrestha J, LeClerq SC, Khatry SK, Jiang T,

Wagner T, et al.Supplementation with micronutrients in

addition to iron and folic acid does not further improve

the hematologic status of pregnant women in rural Nepal.

Journal of Nutrition 2003;133:34928.

Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KP

Jr, et al.Antenatal and postnatal iron supplementation and

childhood mortality in rural Nepal: a prospective follow-

up in a randomized, controlled community trial. American

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Christian P, West KP Jr, Khatry SK, LeClerq SC, Pradhan

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Stewart CP, Christian P, LeClerq SC, West KP Jr, Khatry

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in school-age children in rural Nepal. American Journal of

Clinical Nutrition 2009;90(1):13240.

Stewart CP, Christian P, Schulze KJ, Arguello M, Leclerq

SC, Khatry SK, et al.Low maternal vitamin B-12 status

is associated with offspring insulin resistance regardless of

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Journal of Nutrition 2011;141(10):19127.

Stewart CP, Christian P, Schulze KJ, Leclerq SC, West KP

Jr, Khatry SK. Antenatal micronutrient supplementation

reduces metabolic syndrome in 6- to 8-year-old children in

rural Nepal. Journal of Nutrition 2009;139(8):157581.

Dieckmann 1943 {published data only}

Dieckmann WJ, Adair FL, Michel H, Kramer S, Dunkle

F, Arthur B, et al.Calcium, phosphorus, iron and nitrogen

balances in pregnant women. American Journal of Obstetrics

and Gynecology 1943;47:35768.

Fawzi 2007 {published data only}

Fawzi WW, Msamanga GI, Urassa W, Hertzmark E, Petraro

P, Willett WC, et al.Vitamins and perinatal outcomes

among HIV-negative women in Tanzania. New England

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Friis 2004 {published data only}

Friis H, Gomo E, Nyazema N, Ndhlovu P, Krarup H,

Kaestel P, et al.Effect of micronutrient supplementation on

gestational length and birth size: a randomized, placebo-

controlled, double-blind effectiveness trial in Zimbabwe.

American Journal of Clinical Nutrition 2004;80:17884.

Gupta 2007 {published data only}

Gupta P, Ray M, Dua T, Radhakrishnan G, Kumar R,

Sachdev HP. Multimicronutrient supplementation for

undernourished pregnant women and the birth size of their

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Hininger 2004 {published data only}

Hininger I, Favier M, Arnaud J, Faure H, Thoulon

JM, Hariveau E, et al.Beneficial effects of a combined

micronutrient supplementation on maternal oxidative stress

and newborn anthropometric measurements: a randomised

double blind, placebo-controlled trial in healthy pregnant

women. 21st Conference on Priorities in Perinatal Care in

South Africa; 2002 March 5-8; Eastern Cape, South Africa.

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Hininger I, Favier M, Arnaud J, Faure H, Thoulon JM,

Hariveau E, et al.Effects of a combined micronutrient

supplementation on maternal biological status and newborn

anthropometric measurements: a randomized double-blind,

placebo-controlled trial in apparently healthy pregnant

women. European Journal of Clinical Nutrition 2004;58:

529.

Jarvenpaa 2007 {published data only}

Jarvenpaa J, Schwab U, Lappalainen T, Pakkila M, Niskanen

L, Punnonen K, et al.Fortified mineral water improves folate

status and decreases plasma homocysteine concentration in

pregnant women. Journal of Perinatal Medicine 2007;35(2):

10814. Jarvenpaa J, Schwab U, Lappalainen T, Pakkila M,

Niskanen L, Punnonen K, et al.Mineral water fortified

with folic acid and vitamins B6, B12, D and calcium

improves folate status and decreases plasma homocysteine

concentration in pregnant women. 35th Nordic Congress

of Obstetrics and Gynecology; 2006 May 23-25; Goteburg,

Sweden. 2008:55.

Kaestel 2005 {published data only}

Andersen GS, Friis H, Michaelsen KF, Rodrigues A,

Benn CS, Aaby P, et al.Effects of maternal micronutrient

supplementation on fetal loss and under-2-years child

mortality: long-term follow-up of a randomised controlled



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Osrin 2005 {published data only}

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D, Costello AM, et al.Effect of multiple micronutrient

supplementation during pregnancy on inflammatory

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DS, Adhikari RK, et al.Effects of antenatal micronutrient

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de Lourd

multiple-micronutrient supplementation for women during pregnancy

Documents

multiple micronutrients

placebo o

analyses analysis

low birthweight

gestational age

maternal height

maternal bmi

maternal mortality